The neonate is exposed to the maternal vaginal microbiota during parturition, providing the primary source for normal gut colonization, host immune maturation, and metabolism. These early interactions between the host and microbiota occur during a critical window of neurodevelopment, suggesting early life as an important period of cross talk between the developing gut and brain. Because perturbations in the prenatal environment such as maternal stress increase neurodevelopmental disease risk, disruptions to the vaginal ecosystem could be a contributing factor in significant and long-term consequences for the offspring. Therefore, to examine the hypothesis that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota and on the developing brain, we used genomic, proteomic and metabolomic technologies to examine outcomes in our mouse model of early prenatal stress. Multivariate modeling identified broad proteomic changes to the maternal vaginal environment that influence offspring microbiota composition and metabolic processes essential for normal neurodevelopment. Maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus, the prominent taxa in the maternal vagina. Loss of maternal vaginal Lactobacillus resulted in decreased transmission of this bacterium to offspring. Further, altered microbiota composition in the neonate gut corresponded with changes in metabolite profiles involved in energy balance, and with region- and sex-specific disruptions of amino acid profiles in the developing brain. Taken together, these results identify the vaginal microbiota as a novel factor by which maternal stress may contribute to reprogramming of the developing brain that may predispose individuals to neurodevelopmental disorders.

Maternal stress is a key risk factor for neurodevelopmental disorders, including schizophrenia and autism, which often exhibit a sex bias in rates of presentation, age of onset, and symptom severity. The placenta is an endocrine tissue that functions as an important mediator in responding to perturbations in the intrauterine environment and is accessible for diagnostic purposes, potentially providing biomarkers predictive of disease. Therefore, we have used a genome-wide array approach to screen placental expression across pregnancy for gene candidates that are sex-biased and stress-responsive in mice and translate to human tissue. We identifed O-linked- N -acetylglucosamine (O-GlcNAc) transferase (OGT), an X-linked gene important in regulating proteins involved in chromatin remodeling, as fitting these criteria. Levels of both OGT and its biochemical mark, O - GlcNAcylation, were significantly lower in males and further reduced by prenatal stress. Examination of human placental tissue found similar patterns related to X chromosome dosage. As a demonstration of the importance of placental OGT in neurodevelopment, we found that hypothalamic gene expression and the broad epigenetic microRNA environment in the neonatal brain of placental-specific hemizygous OGT mice was substantially altered. These studies identified OGT as a promising placental biomarker of maternal stress exposure that may relate to sex-biased outcomes in neurodevelopment.

Maternal stress is a key risk factor in neurodevelopmental disorders, which often have a sex bias in severity and prevalence. We previously identified O-GlcNAc transferase (OGT) as a placental biomarker in our mouse model of early prenatal stress (EPS), where OGT levels were lower in male compared with female tissue and were further decreased following maternal stress. However, the function of placental OGT in programming the developing brain has not been determined. Therefore, we generated a transgenic mouse with targeted placental disruption of Ogt (Pl-OGT) and examined offspring for recapitulation of the adult EPS phenotype. Pl-OGT hemizygous and EPS male placentas showed similar robust changes in gene expression patterns suggestive of an altered ability to respond to endocrine and inflammatory signals, supporting placental OGT as an important mediator of EPS effects. ChIP-Seq for the O-GlcNAc mark identified the 17 beta hydroxysteroid dehydrogenase-3 (Hsd17b3) locus in male EPS placentas, which correlated with a reduction in Hsd17b3 expression and concordant reduced testosterone conversion. Remarkably, Pl-OGT adult offspring had reduced body weights and elevated hypothalamic-pituitary-adrenal stress axis responsivity, recapitulating phenotypes previously reported for EPS males. Further, hypothalamic microarray gene-set enrichment analyses identified reduced mitochondrial function in both Pl-OGT and EPS males. Cytochrome c oxidase activity assays verified this finding, linking reduced placental OGT with critical brain programming. Together, these studies confirm OGT as in important placental biomarker of maternal stress and demonstrate the profound impact a single placental gene has on longterm metabolic and neurodevelopmental programming that may be related to an increased risk for neurodevelopmental disorders.M aternal stress early in gestation has been identified as a risk factor for neurodevelopmental disorders, including autism spectrum disorders and schizophrenia. Despite strong epidemiological evidence, there remains a lack of specific mechanisms of disease development or predictive biomarkers of disease risk. Examination of the placenta is a promising avenue to find these mechanisms and biomarkers because of features of its biology and accessibility for diagnostic purposes postparturition. The placenta is uniquely positioned at the interface between the maternal and fetal compartments and is rapidly developing during the period of gestation at which maternal stress has been identified to increase disease risk to the offspring (1-5). We previously identified a reduction in O-GlcNAc transferase (OGT), an important O-glycotransferase enzyme that plays a critical role in regulation of gene expression through chromatin remodeling, in male placentas following early prenatal stress (EPS) (4). Placental OGT is basally lower in males due to its X-linkage and escaping of X-inactivation in the placenta and further reduced in our mouse model of EPS. Additionally, we established that a targeted reduction of placen...

Exposure to prenatal insults such as maternal stress and pathogenic infections has been associated with an increased risk for neurodevelopmental disorders. The mechanisms by which these programing events occur likely involve complex interactions between the maternal hormonal milieu, the placenta, and the developing fetus, in addition to compounding factors such as fetal sex and gestational stage of development. Despite the diverse biological processes involved, examination of common pathways in maternal stress and immune activation offers intriguing possibilities for elucidation of mechanistic insight. Further, the endocrine and sex-specific placenta is a tissue poised to be a key mediator in fetal programing, located at the intersection of the maternal and embryonic environments. In this review, we will discuss the potential shared mechanisms of maternal stress and immune pathway activation, with a particular focus on the important contribution and role of the placenta.

No abstract

Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F 1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F 1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

No abstract

No abstract